Implications of HIV-1 Minority Variants for Virologic Failure and HIV Reservoirs

HIV-1 少数变异对病毒学失败和 HIV 病毒库的影响

• 批准号: 8839187
• 负责人: Jonathan Li
• 金额: $ 13.64万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8839187
• 关键词: AIDS clinical trial group; Accounting; Address; Affect; Alleles; Anti-Retroviral Agents; Area; Biological Assay; Characteristics; Chronic; Clinical; DNA; Data Analyses; Detection; Development Plans; Drug resistance; Evaluation; Failure; Frequencies; Genotype; Goals; HIV; HIV Infections; HIV-1; Hospitals; Immunologics; Individual; Infection; Integrase Inhibitors; K-Series Research Career Programs; Knowledge; Laboratories; Light; Medicine; Mentors; Minority; Modeling; Morbidity - disease rate; Mutation; NNRTI-resistance; Nested Case-Control Study; Participant; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Physicians; Plasma; Population; Population Dynamics; Positioning Attribute; Prevalence; Publishing; RNA; Randomized; Recovery; Regimen; Relative (related person); Research; Research Design; Research Personnel; Resistance; Risk; Ritonavir; Sampling; Scientist; Sequence Analysis; Testing; Time; Treatment Failure; Treatment Protocols; Uncertainty; Variant; Viral; Virus; Woman; Work; antiretroviral therapy; arm; base; career; career development; cost; deep sequencing; experience; fitness; genome analysis; improved; instructor; medical schools; mortality; new technology; non-nucleoside reverse transcriptase inhibitors; resistance mutation; treatment response; viral DNA

DESCRIPTION (provided by applicant): This is an application for a K08 mentored career development award for Dr. Jonathan Li, an Instructor in Medicine at Harvard Medical School and the Brigham and Women's Hospital. Dr. Li is a physician-scientist committed to a career in translational HIV research. He has gathered an experienced team of mentors, collaborators, and advisors and is proposing a comprehensive research, course work, and career development plan that will position him to be a successful independent investigator. The overall goal of Dr. Li's proposed research is to determine the effect of HIV-1 minority variants on the risk of antiretroviral treatment failure and to use minority variant populations to improve our understanding of HIV reservoirs. HIV exists as a diverse cloud of viruses within each infected individual, but current commercial HIV-1 drug resistance tests only take into account mutations present in at least 15-25% of the viral population. However, in a recently published analysis by Dr. Li, minority HIV-1 drug resistance mutations present below the limit of detection of commercial resistance genotyping tests can increase the risk of NNRTI-based therapy failure by more than two-fold. This K08 proposal builds upon these important findings. The main aims are to 1) Determine the prevalence and clinical impact of drug-resistant minority variants within the HIV DNA reservoir; 2) Evaluate the effect of minority integrase inhibitor resistance mutations on the risk of treatment failure; and 3) Characterize fluctuations in HIV-1 RNA and DNA population dynamics in patients with chronic, untreated HIV infection. The knowledge gained from these studies could improve our ability to choose the best treatment regimen for each patient and may help guide strategies for eradicating the HIV reservoir.

描述（由申请人提供）：这是哈佛医学院医学教练乔纳森·李（Jonathan Li）博士以及杨百翰和妇女医院的K08指导职业发展奖的申请。李博士是一位医生科学家，致力于转化艾滋病毒研究的职业。他聚集了一支经验丰富的导师，合作者和顾问团队，并提出了一项全面的研究，课程工作和职业发展计划，这将使他成为成功的独立调查员。 Li博士提出的研究的总体目的是确定HIV-1少数族裔变体对抗逆转录病毒治疗失败风险的影响，并使用少数族裔变体种群来提高我们对HIV储量的理解。 HIV是每个受感染者中一种多种病毒云而存在的，但是当前的商业HIV-1耐药性测试仅考虑到至少15-25％的病毒种群中存在的突变。然而，在LI博士最近发表的分析中，少数HIV-1耐药性突变的存在低于检测商用抗性基因分型测试的极限，可以使基于NNRTI的治疗失败的风险增加了两倍以上。这项K08提案以这些重要发现为基础。主要目的是1）确定HIV DNA储层中耐药少数族裔变体的患病率和临床影响； 2）评估少数积分酶抑制剂耐药性突变对治疗失败风险的影响； 3）表征HIV-1 RNA和DNA种群动力学在慢性，未经治疗的HIV感染患者中的波动。从这些研究中获得的知识可以提高我们为每个患者选择最佳治疗方案的能力，并可能有助于指导消除HIV储层的策略。